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Halogen‐Bonding Interactions of Polybrominated Diphenyl Ethers and Thyroid Hormone Derivatives: A Potential Mechanism for the Inhibition of Iodothyronine Deiodinase
Author(s) -
Marsan Eric S.,
Bayse Craig A.
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201700407
Subject(s) - chemistry , polybrominated diphenyl ethers , deiodinase , halogen bond , iodothyronine deiodinase , halide , halogen , nucleophile , medicinal chemistry , active site , thyroid hormones , hormone , catalysis , organic chemistry , biochemistry , alkyl , pollutant
Abstract Polybrominated diphenyl ethers (PBDEs) increase flame resistance in consumer goods, but these compounds and their hydroxylated derivatives (OH‐BDEs) impair normal thyroid function. Halogen bonding (XB) of PBDEs to an active site selenocysteine may prevent iodothyronine deiodinase(Dio)‐catalyzed activation/deactivation of thyroid hormone (TH) derivatives. In this study, we compare the strength of the XB interactions of TH derivatives, iodine‐based contrast agents and PBDEs/OH‐BDEs with a methylselenolate model of the Dio active site using density functional theory calculations. The strength of the XB interaction depends upon the acceptor halide, the position of the halide, the number of ring substituents, and the proximity of hydroxyl groups to the XB site. The weaker Se⋅⋅⋅Br interactions relative to Se⋅⋅⋅I interactions are consistent with a model of competitive inhibition that blocks binding of THs at elevated PBDE/OH‐BDE concentrations. XB interactions were generally more favorable at ortho and meta positions and in substrates with more electron‐withdrawing substituents. PBDEs/OH‐BDEs that mimic the binding behavior of THs, that is, containing ortho and meta bromides and adjacent hydroxyl groups, may be the most effective inhibitors. Highly‐brominated PBDEs/OH‐BDEs have comparable interaction energies to THs and may undergo debromination. These results may also suggest that XB strength must exceed a threshold value in order for PBDEs/OH‐BDEs to undergo nucleophilic attack by Dio.